Zelek L, Barthier S, Riofrio M, Fizazi K, Rixe O, Delord J P, Le Cesne A, Spielmann M
Department of Medicine, Institut Gustave-Roussy, Villejuif, France.
Cancer. 2001 Nov 1;92(9):2267-72. doi: 10.1002/1097-0142(20011101)92:9<2267::aid-cncr1572>3.0.co;2-q.
Currently, there is no gold standard for the treatment of patients with metastatic breast carcinoma who have experienced failure with anthracyclines and taxanes. A biologic rationale suggests that the mechanism of taxane resistance could be because of an excess of depolymerized tubulin that could enhance sensitivity to vinorelbine. The objective of the study was to assess the tolerance and efficiency of weekly vinorelbine in metastatic breast carcinoma after failure with taxanes.
Patients with measurable disease, a World Health Organization performance status of less than 3 and a life expectancy longer than 3 months were eligible. Persistent taxane-induced neuropathy higher than Grade 1 was an exclusion criterion. The initial planned dose was 30 mg/m(2)/week on an outpatient basis without granulocyte colony-stimulating factor (G-CSF). Neutrophil and platelet counts of 1.0 and 80 g/L, respectively, were required before each new injection; otherwise vinorelbine was delayed for 7 days with a dose reduction of 5 mg/m(2) at the second episode. The dose also was reduced if Grade 3 or 4 toxicity occurred. If the adverse event persisted or if the delay exceeded 14 days between 2 injections given at a dose of 20 mg/m(2), vinorelbine was definitively discontinued.
Between November 1997 and March 1999, 40 patients with a median age of 49 (range, 39-69) were enrolled. All of them had previously received anthracyclines and taxanes. Because of the delays in neutrophil recovery, the median dose intensity did not exceed 22.5 mg/m(2)/week (range, 11.25-30), and the initial planned dose of 30 mg/m(2)/week appeared unfeasible without G-CSF. The starting dose therefore was 25 mg/m(2)/week after the first 6 patients. Neutropenia led to fever in only three patients. Other severe toxicities were Grade 2-3 neuropathy (n = 5), Grade 2-3 ileus (n = 7), Grade 3 anemia (n = 4), and Grade 3 sepsis (n = 1). Objective responses were observed in 10 of 40 patients (25%), 7 of whom had visceral metastases and 4 who were refractory to taxanes (including 2 patients with liver involvement > 50%). The median time to failure was 6 months (range, 4-12) for responding patients. Disease stabilization was achieved in 9 patients (23%) for a median duration of 5 months (range, 4-6). The median survival duration for the whole population was 6 months (range, 2-18+).
Weekly vinorelbine is an active salvage therapy for metastatic breast carcinoma after failure with anthracyclines and taxanes, even in patients with taxane-refractory metastatic breast carcinoma. This confirms that vinorelbine and taxanes are not cross-resistant.
目前，对于蒽环类药物和紫杉烷类药物治疗失败的转移性乳腺癌患者，尚无金标准治疗方案。生物学原理表明，紫杉烷耐药的机制可能是由于解聚微管蛋白过多，这可能会增强对长春瑞滨的敏感性。本研究的目的是评估在紫杉烷类药物治疗失败后，每周使用长春瑞滨治疗转移性乳腺癌的耐受性和疗效。
符合条件的患者需有可测量病灶，世界卫生组织体力状况评分小于3，预期寿命超过3个月。持续存在高于1级的紫杉烷诱导的神经病变为排除标准。初始计划剂量为30mg/m²/周，门诊给药，不使用粒细胞集落刺激因子（G-CSF）。每次新注射前，中性粒细胞计数需达到1.0×10⁹/L，血小板计数需达到80×10⁹/L；否则，长春瑞滨推迟7天给药，第二次推迟时剂量减少5mg/m²。如果发生3级或4级毒性反应，剂量也需减少。如果不良事件持续存在或两次20mg/m²给药之间的延迟超过14天，则最终停用长春瑞滨。
1997年11月至1999年3月，纳入了40例患者，中位年龄49岁（范围39 - 69岁）。所有患者此前均接受过蒽环类药物和紫杉烷类药物治疗。由于中性粒细胞恢复延迟，中位剂量强度未超过22.5mg/m²/周（范围11.25 - 30），且在不使用G-CSF的情况下，初始计划的30mg/m²/周剂量似乎不可行。因此，在前6例患者之后，起始剂量为25mg/m²/周。仅3例患者因中性粒细胞减少导致发热。其他严重毒性反应包括2 - 3级神经病变（n = 5）、2 - 3级肠梗阻（n = 7）、3级贫血（n =
4）和3级败血症（n = 1）。40例患者中有10例（25%）观察到客观缓解，其中7例有内脏转移，4例对紫杉烷类药物耐药（包括2例肝脏受累>50%的患者）。缓解患者的中位疾病进展时间为6个月（范围4 - 12个月）。9例患者（
23%）病情稳定，中位持续时间为5个月（范围4 - 6个月）。整个人群的中位生存时间为6个月（范围2 - 18 +个月）。
对于蒽环类药物和紫杉烷类药物治疗失败的转移性乳腺癌患者，每周使用长春瑞滨是一种有效的挽救治疗方法，即使是对紫杉烷类药物耐药的转移性乳腺癌患者。这证实了长春瑞滨和紫杉烷类药物不存在交叉耐药。
